Synthesis of chiral disulfides: Potential reagents for enantioselective sulfurization

Article abstract of DOI:10.1080/17415993.2011.580346

Synthesis of chiral phosphorothioates for use as antisense oligonucleotides might benefit from the use of chiral disulfides. This paper reports the synthesis of chiral analogs of phenylacetyl disulfide and of 5-methyl-3H-1,2,4-dithiazol-3-one from the same set of 2-arylalkanoic acids. The X-ray crystal structures of the disulfides derived from (R) and [S]-2-phenylpropanoic acid establish the stereochemistry and the helicity of these materials, and density functional theory calculations suggest that the high specific rotations can be due to preferred retention of this helicity in solution. Chiral HPLC showed that the final products were formed with enantiomeric purities from 86.1% to >99.9%.

Full text of DOI:10.1080/17415993.2011.580346

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Synthesis of chiral disulfides: potential
reagents for enantioselective
sulfurization
Joshua A. Mukhlall a , Bruce C. Noll b & William H. Hersh a
a Department of Chemistry and Biochemistry , Queens College
and the Graduate Center of the City University of New York ,
Flushing , NY , 11367–1597 , USA
b Bruker AXS, Inc., 5465 East Cheryl Parkway, Madison , WI ,
53711 , USA
Published online: 19 May 2011.
To cite this article: Joshua A. Mukhlall , Bruce C. Noll & William H. Hersh (2011) Synthesis of chiral
disulfides: potential reagents for enantioselective sulfurization, Journal of Sulfur Chemistry, 32:3,
199-212, DOI: 10.1080/17415993.2011.580346
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Journal of Sulfur Chemistry
Vol. 32, No. 3, June 2011, 199–212
Synthesis of chiral disulfides: potential reagents for
enantioselective sulfurization
Joshua A. Mukhlalla, Bruce C. Nollb and William H. Hersha*
aDepartment of Chemistry and Biochemistry, Queens College and the Graduate Center of the City University
of New York, Flushing, NY 11367–1597, USA; bBruker AXS, Inc., 5465 East Cheryl Parkway, Madison,
WI 53711, USA
(Received 25 February 2011; final version received 7 April 2011)
Synthesis of chiral phosphorothioates for use as antisense oligonucleotides might benefit from the use
of chiral disulfides. This paper reports the synthesis of chiral analogs of phenylacetyl disulfide and of
5-methyl-3H-1,2,4-dithiazol-3-one from the same set of 2-arylalkanoic acids. The X-ray crystal structures
of the disulfides derived from (R) and (S)-2-phenylpropanoic acid establish the stereochemistry and the
helicity of these materials, and density functional theory calculations suggest that the high specific rotations
can be due to preferred retention of this helicity in solution. Chiral HPLC showed that the final products
were formed with enantiomeric purities from 86.1% to >99.9%.
Keywords: chiral disulfides; X-ray; chiral HPLC; phosphorothioate oligonucleotides
1. Introduction
Sulfurization of phosphorus is a key step in the synthesis of phosphorothioate oligonucleotides,
reagents that can be used as DNA analogs for antisense applications (1–4). While elemental
sulfur can be used, it was noted long ago that it is relatively slow and, when used in an automated
DNA synthesizer, “led to instrument failure as a result of the insolubility of S8 in most organic
solvents” (5). Beaucage solved this problem in 1990 with the report of a soluble reagent, now
popularlyknownastheBeaucagereagent(Figure 1), thatrapidlydeliveredsulfurtothephosphorus
of the phosphite triester in the phosphoramidite method of solid-phase DNA synthesis (5, 6).While
*Corresponding author. Email: william.hersh@qc.cuny.edu
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2011 Taylor & Francis
DOI: 10.1080/17415993.2011.580346
http://www.informaworld.com

200 J.A. Mukhlall et al.
Figure 1. Examples of sulfurizing reagents.
effective, many reports have noted its poor stability in solution (necessitating its use in silylated
glass (6)), difficult synthesis resulting in high cost, and formation of an oxidizing reagent as a
byproduct, which may account for small amounts of phosphate impurity linkages (7–10). In order
to overcome these problems, a wide variety of sulfurizing reagents, a selection of which is shown
in Figure 1, has been investigated (7–28).
Since substitution of a terminal oxygen with a sulfur atom on the phosphate backbone of
DNA results in a loss of symmetry at the phosphorothioate linkage, a mixture of diastereomeric
linkages results from the sulfurization of the phosphite triester. For one reagent that has been
successfully used by Isis Pharmaceuticals, phenylacetyl disulfide (PADS), it was shown that the
diastereomer ratio was indistinguishable from that obtained using the Beaucage reagent (29, 30).
Inprinciple, anachiralreagentcouldselectivelygiveonediastereomeratearlyreaction, butachiral
sulfurizing reagent might do so more readily by double stereodifferentiation (31). A recent report
by Mikolajczyk described the use of chiral disulfides for kinetic resolution of phosphines (32), so
a similar approach involving the synthesis of chiral analogs of reagents used for phosphorothioate
synthesis seemed warranted.
The Beaucage reagent itself does not appear to be a good choice for the synthesis of a chiral
analog, but both PADS and 5-methyl-3H-1,2,4-dithiazol-3-one (MEDITH) (33),1 another highly
reactive sulfurizing reagent, presented ready opportunities for the convergent synthesis of chiral
reagents; the other reagents would place centers of chirality farther from the reactive disulfide
linkage. We report here (1) the synthesis of enantiomerically pure chiral analogs of PADS starting
with known α-alkylated carboxylic acids, (2) X-ray diffraction results for one pair of enantiomers
that unequivocally establish the absolute configurations of two disulfides and are in accord with
the reported configurations of the starting carboxylic acids, (3) density functional theory (DFT)
calculations that support the observed helicity about the S–S bond, (4) conversion of the enan-
tiomerically pure chiral acids to chiral thioamides with no epimerization in cases where there is
relatively little steric encumbrance, (5) conversion of the thioamides to acid-sensitive enantiomer-
ically pure chiral analogs of MEDITH, and (6) chiral HPLC results in support of the enantiomeric
purity of the new disulfides. We will report separately the results of phosphite sulfurization with
these new reagents (34).2
2. Results and discussion
2.1. Chiral analogs of PADS
The synthesis of PADS from phenylacetyl chloride has been reported by several groups
(12, 35–37). Since enantiomerically pure 2-aryl carboxylic acids are well known, this seemed
to be a straightforward route to the desired chiral disulfides. The method developed by Kodomari
et al. (35), which gave PADS in 95% yield, was carried out by the addition of an aqueous solution of
Na2S2 to a benzene solution of phenylacetyl chloride and hexadecyltributylphosphonium bromide
as a phase-transfer catalyst. When this method was used for the synthesis of the chiral analogs of
PADS using chiral carboxylic acid chlorides (38), crude yields of only ∼60–70% were obtained.
This could be improved to ∼80–90% simply by the addition of the acid chloride to a vigorously

Journal of Sulfur Chemistry 201
stirred mixture of aqueous Na2S2 and the phase-transfer catalyst in toluene (Scheme 1). A single
crystallization of 2a–c in methanol and of 2d in benzene/petroleum ether gave the enantiomers
in 50–63% isolated yields. The specific rotations of the disulfides are unusually high, ranging
from an average of 366 for 2a to 541 for 2c.
Scheme 1. Synthesis of chiral disulfides.
2.2. X-ray structure of 2a and DFT calculations
Single crystals of (R, R) and (S, S)-2a were grown by a single crystallization from hot methanol
with cooling to room temperature (rt).The X-ray structure determinations confirmed both the over-
all structures and on the basis of Flack parameters (39, 40) unequivocally established the absolute
stereochemistry of the α-stereocenters of the carboxylic acids, namely, (R)-(-)-1a (41–43) giving
rise to (R, R)-(-)-2a and (S)-(+)-1a giving rise to (S, S)-(+)-2a (see Figure 2 for a representative
ORTEP drawing (44) and the supplementary data for details; there are two independent molecules
in the unit cell, differing slightly in the dihedral angles about the carbonyl to 3◦–carbon bonds
and the tilt of the phenyl rings).3 The absolute configurations of the starting carboxylic acids were
reported in 1956 without the use of a single-crystal X-ray diffraction structure (41), and other
workers have reported results in agreement with this determination: each of the (+)-enantiomers
Figure 2. ORTEP drawing of Molecule 1 (see text) of (S,S)-2a.

202 J.A. Mukhlall et al.
of 1a–e is accepted as having the S-configuration (41–43, 45, 46). A search of the Cambridge
Structural Database for structures of 2-phenylpropanoic acid (1a) turned up several structures of
diastereomeric salts and of the pure enantiomers in cocrystals, but the absolute configurations
were all assumed to be correct and no attempts to crystallographically confirm the R- and S-
configurations were reported (47–50). However, we did find one other case comparable to those
of (R, R) and (S, S)-2a in which an ester derived from (S)-(+)-1a was subjected to a Flack
analysis and the absolute configuration confirmed (51).
Returning now to the disulfides themselves, a search of the Cambridge Structural Database
for disulfides having carbonyl groups on the disulfide linkage resulted in finding eight neutral
acyclic compounds of the form RC(O)SSC(O)Rꢀ (Table 1). Most of the R groups are aromatic
(i.e. R = Rꢀ = Ph (3a) (52, 53), 4-chlorophenyl (3b) (54), 2-methoxyphenyl (3c) (55), 1-indolyl
(3d) (56), ferrocenyl (3e)) (57), one has R = Rꢀ = (cyclohexyl)2N (3f) (58), and two have R = F
and Rꢀ = CF3 (3g), CF2Cl (3h) (59, 60). The disulfide bond lengths fall in a fairly tight range
(2.013Å for 3d to 2.039(2)Å for 3c), so those for (R, R)-2a (2.0381(9), 2.037(1)Å) and for
(S, S)-2a (2.0408(6), 2.0416(7)Å) are relatively long. The C–S–S–C dihedral angles range from
77.7(2)◦ for 3g to 92.2(3)◦ for 3e, averaging 84.2 4.7◦. Here, the dihedral angles for (R, R)-2a
(−77.5(1)◦, −81.2(1)◦) and (S, S)-2a (+77.29(8)◦, +81.24(8)◦) fall at the acute end of the range.
Finally, we note that in all cases, the CO bonds of the carbonyl groups very nearly eclipse the
disulfide bond; the absolute values of the O–C–S–S dihedral angles range from 0.1(2)◦ (2a) to
10.7(6)◦ (3c). Overall, the bond lengths and dihedral angles in 2a are comparable not just to
the above dicarbonyl disulfides, but also to those in a variety of disulfides (53, 61), including a
representative sampling of 25 neutral acyclic RC(S)SSC(S)R structures found in the Cambridge
Structural Database (62–66) (but for R = alkoxy the C=S moieties do not eclipse the disulfide
bond (67, 68)). As discussed by Zysman-Colman and Harpp (69), the near 90◦ dihedral angle
in X–S–S–X systems arises from the fact that the bonds are mostly p in character, and so lone
pair–lone pair repulsion from the electrons in non-bonding p-orbitals on the adjacent sulfur atoms
is minimized, while p–σ∗ overlap between the p-electrons and the S–X σ∗ orbitals is maximized.
The solid-state structures of 2a exhibit opposite helicity about the S–S bond, namely P (i.e. a
“plus” sign for the C–S–S–C dihedral angle, that is, clockwise rotation of the carbonyl moieties
Table 1. Structural data (X-ray and DFT calculations) for dicarbonyl disulfides, RC(O)SSC(O)Rꢀ.
Compound
R, Rꢀa
S–S (Å) ∠(CSSC) (◦) ∠(SSCO1) (◦) ∠(SSCO2) (◦)
Space group/DFTb
P21/ac
3a (52, 53)
3b (54)
3c (55)
3d (56)
3e (57)
3f (58)
Ph
2.021(2)
2.021(8)
2.039(2)
2.013(1)
80.8(3)
79.1(1)
84.7(3)
85.4
92.2(3)
89.7(1)
77.7(2)
84.2(2)
−77.5(1)
−81.2(1)
77.29(8)
81.24(8)
81.78
7.8(5)
−2.9(3)
−3.5(5)
−2.0
−9.2(5)
−10.3(3)
−10.7(6)
−12.4
¯
4-ClC6H4
2-MeOC6H4
1-indolyld
(C5H5)Fe(C5H4) 2.022(2)
(C6H12)2N
F, CF3
P1
Pbca
P21/c
P212121
C2/c
P21/n
P21/n
P1211
−0.6(5)
−3.2(2)
−6.1(4)
0.8(4)
−9.4(5)
−3.2(2)
8.0(5)
2.014(1)
2.017(2)
2.029(1)
2.0381(9)
2.037(1)
2.0408(6)
2.0416(7)
2.069
3g (59)
3h (60)
F, CF2Cl
Ph(CH3)CH
4.8(3)
(R, R)-2ae
4.3(2)
0.4(2)
−5.0(2)
6.7(2)
(S, S)-2ae
Ph(CH3)CH
Ph(CH3)CH
−4.4(2)
−0.1(2)
−3.47
0.87
−5.18
5.5(2)
P1211
−6.9(2)
(S, S)-2a, DFT
−3.49
Gas phase
Gas phase, 0.72 kcal/mol
CH2Cl2
2.070
2.070
−84.52
0.88
90.10
−5.81
2.072
−90.04
−0.36
−0.50
CH2Cl2, 0.84 kcal/mol
Notes: aR = Rꢀ where only one R group is given.
bStructures at local minima, and energies relative to the preceding structure.
cData from (52); see text.
dData from Cambridge Structural Database.
eData given for two independent molecules in the unit cell.

Journal of Sulfur Chemistry 203
from front to back on looking down the S–S bond, or alternatively S ) for (S, S)-2a and M (i.e.
S-S
for “minus”, or R ) for (R, R)-2a (70). The major difference between 2a and the compounds
S-S
3a–h is that only 2a is non-racemic, and so only for 2a are the signs of the dihedral angles
important. That is, for 3a–h, either both the P and M forms must be present in the crystal, or if
the compound crystallizes in a chiral space group, we presume both enantiomorphs of the crystals
were present. In fact, the latter must be the case for 3e, which crystallizes in the chiral space group
P 212121, and by chance two structures have been reported. While the authors did not comment
on this, one is P (57) and the other is M (71), and data for the structure with the smaller R-factor
value is given in Table 1. In addition, one structure, that of 3a, was refined in a centrosymmetric
space group (P 21/c), yet was described as having “right-handed chirality” which would imply
a single enantiomer; the published packing diagram in fact showed identical chiral molecules,
which would not be possible in P21/c (53). The structure of 3a (refined in P21/a) had been
reported previously with essentially the same molecular structure (52), but no packing diagram
was published. While the data are in line with the other structures, the values must be viewed with
caution.
While it seems most unlikely that (R, R) and (S, S)-2a are atropisomers – that is, that they
do not interconvert with respect to rotation about the S–S bond – the high specific rotations
noted for each of the disulfides could be due to a preferred helicity in solution driven by the
stereogenic centers. DFT calculations (72) were carried out to assess the relative energies of
P -(S, S)-2a and M-(S, S)-2a. The (S,S)-isomer was first optimized (6-31+G(d), B3LYP) start-
ing from the X-ray coordinates of Molecule 1, to give a structure that was little changed (S–S
2.069Å, ∠(C–S–S–C) + 81.8◦; Table 1). Rotation about the S–S bond followed by reoptimization
(6-31+G(d), B3LYP) gave a local minimum with virtually the same S–S bond length (2.070Å) and
a C–S–S–C dihedral angle of −84.5◦. The energies of the optimized structures were calculated at
the 6-311+G(2d,p) level again using the B3LYP functional, and the energy of this M conformation
of (S, S)-2a was calculated to be 0.72 kcal/mol higher than that of P-(S, S)-2a. The optimizations
were then repeated, using solvation (polarizable continuum model (PCM) model) in methylene
chloride, since that solvent was used to measure the optical rotations, and the two minima were
located but with modest changes in the dihedral angles (approximately 90◦; Table 1), and there
was a small predicted increase (to 0.84 kcal/mol) in the change in energy upon rotation (Figure 3).
While the two structures look different with respect to the orientations of the phenyl rings, in fact
there is only a small change in the S–C–C–C(Ph) dihedral angles, and hence in the conformation
about the carbonyl to 3◦–carbon bond. The P minimum was difficult to find because the potential
Figure 3. Calculated structures (optimized using DFT, 6-31+G(d), B3LYP) of P–(S,S)-2a (a) and M–(S,S)-2a
(b) with solvation by CH2Cl2 (PCM). In both (a) and (b), the carbonyl on the left and the two sulfur atoms are
=
approximately in one plane; in (a) the carbonyl on the right is in front of the C( O)SS plane, while in (b) it is
behind. In (a) ∠(S–C–C–C(Ph)) = −88.9, −89.9◦, and in (b) −97.8, −98.2◦; in the X-ray structure of (S,S)-2a,
∠(S–C–C–C(Ph)) = −88.7(1), −103.2(1)◦ in Molecule 1, and −80.2(1), −92.2(1)◦ in Molecule 2.

204 J.A. Mukhlall et al.
energy surface appeared to be quite flat, with another minimum at ∠(C–S–S–C) = 83.47◦, which
was 0.18 kcal/mol higher in energy than the 90.10◦ minimum, but the calculation kept optimizing
to an apparent local energy maximum found at ∠(C–S–S–C) ≈ 87.7◦, which was energetically
0.01 kcal/mol higher. Nevertheless, both in the gas phase and in solution, the ∼0.8 kcal/mol
energy difference between the rotamers is in agreement with the observed solid state structure.
However, it confirms the supposition that these are not likely to be true atropisomers, but the
difference could certainly give a preference in solution and account for the high optical rota-
tions of the disulfides. Interestingly, the one related enantiomerically pure disulfide, which has
a thiocarbonyl RC(S)SSC(S)R core (R = (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentene), has
20
an even larger optical rotation ([α]D − 2102) (73); here too the X-ray structure was reported, but
it appears that the more crowded atropisomer was observed in the solid state.
2.3. Synthesis of chiral analogs of MEDITH
Chiral sulfurizing reagents based on the MEDITH structure (Figure 1) are attractive for a
number of reasons. First, MEDITH and a related ethoxy (in place of the methyl)-substituted
analog are particularly reactive (19, 20). In our hands, for instance, the phosphorus of a chi-
ral N-sulfonylvaline-derived oxazaphospholidinone (74) was sulfurized by MEDITH while the
Beaucage reagent did not react (75). Second, the structure of MEDITH is arguably the most dif-
ferent from those of the acyclic di and tetrasulfides shown in Figure 1 and therefore chiral analogs
provide the greatest opportunities for different results from the PADS analogs. Third, the starting
materials for the synthesis of the MEDITH analogs are the same as the chiral carboxylic acids
1a–d used for the PADS analogs.
ThechiralcarboxylicacidsshowninScheme 2wereconvertedtotheacidchlorides(38)andthen
treated with concentrated NH4OH (42) to give the chiral amides (4a–e), for which literature data
are available, albeit from alternate synthetic routes that generally did not give both enantiomers
(45, 46, 76, 77). The conversions of the chiral amides to the thioamides were initially attempted
with Lawesson’s reagent (78), but only racemic products were isolated. The problem was traced
to racemization of the thioamides on silica gel (79), even on silica gel treated with 1% Et3N. Since
the use of Lawesson’s reagent required purification by column chromatography, other methods
were tried, including P4S10 alone (80), P4S10 on basic alumina (80), and P4S10/Na2CO3 (81). The
P4S10/Na2CO3 procedure gave the highest yields and it did not require column chromatography,
the purification of the products instead being carried out by an aqueous work-up followed by
crystallization. The α-methyl- and ethyl-substituted chiral amides 4a, b, d, and e were converted
in this way to the new thioamides 5a, b, d, and e in 85–95% yield. Only the i-Pr-substituted 4c
Scheme 2. Synthesis of MEDITH analogs.

Journal of Sulfur Chemistry 205
failed to react with P4S10/Na2CO3, even after stirring for longer times or at reflux. It is reasonable
to suppose that the “adamantane-like” structure of P4S10 gives too much steric hindrance with
the relatively bulky isopropyl group. In this case for the conversion to the thioamide, Lawesson’s
reagent was used followed by chromatography on neutral alumina (rather than silica) treated
with 1% Et3N, and modest 43–48% yields of the enantiomers of 5c were obtained following
crystallization. Not surprisingly, however, as will be seen below, the enantiomeric purities of 5c
were lower than those of the other thioamides.
The synthesis of MEDITH or analogs with different substituents at the 5-position has been
reported previously (82–86), and we chose Barany’s procedure (85) since it was used to pre-
pare material for phosphite triester sulfurization (20). This method gave only a ∼10% yield
when applied to the synthesis of (S)-6d, so optimization of the reaction was attempted using
achiral 2-phenylethanethioamide. It immediately became apparent that Barany’s procedure using
thioacetamide essentially fails for the 2-phenyl-substituted analog – only traces of the product
were detected by NMR following the initial reaction, which gave a dark gum. Switching solvent
from dimethoxyethane to methylene chloride or acetonitrile gave the same result. Racemic 2-
phenylpropanethioamide was tried next, both at rt and at −35◦C (the literature conditions were
<10◦C), with both normal and inverse addition of reactants, but again only traces of the product
formed.
During the course of these experiments, we observed that a mixture of triethylamine and
chlorocarbonylsulfenyl chloride in dimethoxyethane appeared to react and gave a dark solution,
so an rt reaction of 2-phenylpropanethioamide and chlorocarbonylsulfenyl chloride was run in
the absence of the base. To our surprise, the reaction was complete within 5 min, as judged by
1H NMR and TLC. When this method was used starting with (S)-5d, the product 6d was in fact
isolated in ∼95% yield, but it was found to be racemic. Evidently, the two equivalents of HCl
produced must be sequestered to prevent racemization, but a milder base than triethylamine was
required to prevent reaction with the chlorocarbonylsulfenyl chloride. Pyridine was found to be
effective, and ether was used as the solvent to facilitate removal of the pyridinium chloride salt; in
this way, optically active material was formed in ∼95% crude yield. Compounds (S)-6d and both
enantiomers of 6a were isolated in 92% and 60% yields, respectively, following crystallization,
while both enantiomers of each of 6b, c, and e were obtained as viscous oils that did not solidify,
in 85–92% yield.
The acid sensitivity of the MEDITH analogs toward racemization was not anticipated and
would not be observable directly in the parent compound. We presume that the enol tautomer
is relatively stable and that this accounts for the observed racemization, although even without
enol formation, related epimerization in acid has been observed at a stereocenter attached to the
C=N moiety of a five-membered oxazole heterocycle (87). We briefly examined the reaction of
MEDITH itself in CDCl3 with D2O/HCl, but in fact no deuterium incorporation took place under
these conditions and we have not pursued this further.
2.4. Enantiomeric purity of disulfides
The starting materials for the new disulfides described here, the chiral carboxylic acids 1a–e, have
all been reported, along with their enantiomeric purities and a variety of optical rotations for some
of the individual acids. Determination of the optical purity of the starting acids on the basis of
optical rotation was therefore somewhat uncertain; our values and literature values may be found
in the supplementary data, along with data for the diastereomeric salts and amides. Regardless of
the starting material purity, chiral HPLC is necessary for determining the enantiomeric purity of
the disulfide products, and as will be seen below in at least some cases, high enantiomeric purity
can be achieved.

206 J.A. Mukhlall et al.
For disulfides 2a–d, it is necessary to separate the meso and racemic mixture by chiral HPLC.
In all cases, it was necessary to prepare this mixture by the synthesis of the disulfides from the
racemic acid. For naproxen-derived 2d where the racemic acid was not the starting material,
the mixture was prepared by racemization of 1d with DBU at 120◦C (88). We found that these
mixtures could be separated on the new Chiral Technologies bonded CHIRALPAK® IB column,
but the separation for 2a–c was remarkably sensitive to minor changes in the percentage of 2-
propanol in hexane (0.25% at 25◦C gave excellent results); for 2d, the mixture was separated
by eluting with 8% acetone in hexanes. In two cases, we have detected 0.09% and 0.03% of the
wrong enantiomer or the meso isomer as impurities, so we conservatively estimate a detection
limit of >0.1%; these values are uncorrected for any potential differences in the absorbance of
the meso diastereomers. The enantiomeric purities of the PADS analogs ranged from 98.99% for
(S, S)-2c to >99.9% for (S, S)-2a and (S, S)-2b. Each of the PADS analogs is a solid, and can
benefit from purification by removal of the “wrong” enantiomer of the chiral acid chlorides in the
disulfide reaction by removal of any of the meso diastereomer that forms.
Both the new chiral thioamides 5a–e and the MEDITH analogs 6a–e were similarly analyzed
by chiral HPLC. The racemic mixtures were prepared by simply mixing the enantiomers for all
but the naproxen-derived compounds 5d and 6d; for 5d, the racemic mixture was prepared by
stirring a mixture of (S)-5d and silica gel in CH2Cl2 for 1 h, and for 6d, the racemic mixture
was prepared by reaction of (S)-5d and ClSC(O)Cl in the absence of pyridine. The enantiomeric
purities of the thioamides ranged from 88.9% and 85.8% for (R) and (S)-5c to >99.9% for (R) and
(S)-5b; enantiomer separations were easily achieved for 5a–c and e on CHIRALPAK® IB eluting
with 10% acetone in hexanes at 20◦C. However, for 5d, we were unable to find any conditions
for separation of the enantiomers on any of CHIRALPAK® IA, B, or C. For the final MEDITH
analogs, the enantiomeric purities ranged from 88.5% and 86.1% for (R) and (S)-6c to 99.1%
and 99.4% for (R) and (S)-6a. Separation of these enantiomers was much more difficult and
was achieved on CHIRALPAK® IA or B eluting with 0.25–1% methanol or ethanol in hexanes
at temperatures from 12◦C to 25◦C except for 6d, which was carried out with 8% acetone in
hexanes at 20◦C on CHIRALPAK® IC. While we were concerned that racemization might be
occurring on-column during the HPLC runs, no change in enantiomer ratios was detected when
we decreased the column contact time by eluting at higher flow rates.
In order to evaluate the enantioselectivities of the disulfide-forming syntheses, enantiomeric
purity data are collected in Table 2. Values for each compound were determined either by com-
parison of observed specific rotation to literature values (for 1 and 4) or by HPLC as described
above (for 2, 5, and 6). The comparison of the PADS analogs to the precursor chiral carboxylic
acids shows that each of the disulfides has equal or greater enantiomeric purity, so not only is
there no evidence of epimerization, but as expected, the enantiomeric purity can be enhanced by
removal of the meso (and racemate) by crystallization, as particularly seems to be the case for
(R)-1a conversion to (R, R)-2a. The conversions of the acids to the amides consistently gave
similar enantiomeric purities (average deviation 0.5%) except for 1e to 4e, but given the higher
enantiomeric purities for 5e and 6e, it is more likely that the specific rotations are in error. The
HPLC values for the thioamides are, with two exceptions, remarkably similar to the [α]D values
for the acids (average deviation 1.4%); the exceptions are for the α-isopropyl cases where the
thioamide syntheses necessitated the use of Lawesson’s reagent, which gave a significant drop in
enantiomeric purity on going from the amides (4c) to the thioamides (5c). The P4S10/Na2CO3
method, in contrast, clearly proceeded with high retention of enantiopurity, as seen for the overall
conversion of 1a, b, and e to 4a, b, and e. Last, the conversions of the thioamides to the MEDITH
analogs proceeded with comparable (or better) enantiomeric purity for 5a, c, e to 6a, c, and e;
for 5a to 6a, the purity improved, suggesting that like the PADS case, crystallization must serve
to remove some racemate. On the other hand, there was a drop in purity on going from the α-2-
phenylbutane case 5b to 6b, and a smaller but still noticeable drop for the naproxen case 4d to

Journal of Sulfur Chemistry 207
Table 2. Enantiomeric puritya of chiral precursors and disulfides.
Compound
Acid (1)b
PADS (2)c
Amide (4)b
Thioamide (5)c
MEDITH (6)c
(R)-a
(S)-a
(R)-b
(S)-b
(R)-c
(S)-c
(S)-d
(R)-e
(S)-e
91.7
99.9
97.2
>99.9
97.9
98.7
99.4
97.6
95.8
99.4
>99.9
99.4
>99.9
99.9
92.8
98.9
95.8
>99.9
97.3
98.4
100
91.3
98.2
>99.9
>99.9
88.9
99.1
99.4
91.3
91.2
88.5
86.1
94.9
96.3
96.5
99.0
99.4
85.8
89.7
88.2
98.7
93.5
Notes: aEnantiomeric purity = [major configuration]/[(R) + (S) + meso] × 100.
bEvaluated from observed [α]D by comparison to literature values; see supplementary data for data used. Literature data were
averaged if more than one value was available, (R) and (S) values were combined where available and included in the average,
and corrected for HPLC %ee when available. In cases where our observed [α]D was higher than the literature value, it was
taken as 100% enantiomeric purity and [α]D for the opposite configuration was compared with this new 100% value.
cEvaluated from chiral HPLC data; see supplementary data for HPLC conditions and chromatograms.
6d. In the naproxen case, we were unable to resolve the thioamide enantiomers, so we can only
guess that the loss occurred at this stage, rather than the acid to amide stage. In any case, there is
no explanation for these modest differences. For instance, while 6b is an oil and so presents no
opportunity for crystallization-enhanced purity, 6e is also an oil and formed in high enantiomeric
purity; 6d on the other hand is a solid, just like 6a, which gave the highest enantiomeric purity.
3. Conclusion
Conversion of α-alkyl-substituted phenyl acetic acids to diacyl disulfides is readily carried out to
give the desired compounds in >99.0% enantiomeric purity. The absolute configurations of the
methyl-substituted compounds (R) and (S)-2a were unequivocally established by single-crystal
X-ray diffraction. The high specific rotations ([α]D ≈ 360–540) suggest that the helicity about the
S–S bond observed in the solid state may be preferentially retained in solution. Conversion of the
same set of chiral carboxylic acids to thioamides without racemization could best be carried out by
avoidance of both acidic conditions and chromatography; specific rotation and HPLC data showed
this could be accomplished using P4S10 under basic conditions but not with Lawesson’s reagent.
Conversion of the thioamides to the MEDITH analogs was carried out in much higher yield than
previously described, by using pyridine rather than triethylamine to sequester the HCl generated
during the reaction. The heterocycles, which were formed in up to ∼99% enantiomeric purity,
were quite sensitive toward acid-induced racemization, and so while six of the cases proceeded
with comparable enantiomeric purity upon conversion of the thioamides, three gave up to 9%
lower enantiomeric purities. Work on the results of reactions of these new chiral disulfides with
dinucleoside phosphite triesters will be reported separately (34).
4. Experimental section
4.1. Carboxylic acids, acid chlorides, and amides
Resolutions of racemic 1a (41), 1b (41), 1c (42), and 1e (88) were carried out as described in the
referenced papers, except that for 1e the starting point was the racemate rather than the partially
enriched material. Racemic 1b was synthesized using the method described for 1c (42), and 1c
was prepared using the literature procedure (42). Racemic 1e was obtained by ether extraction
from commercial ibuprofen tablets, and (S)-1d was isolated from commercial sodium naproxen

208 J.A. Mukhlall et al.
tablets by ether extraction from an aqueous acidic solution of the powdered material. In all cases,
the procedure used for 1e (88) was employed to regenerate the acid from the diastereomeric
α-methylbenzylamine salts (i.e. via hydrolysis with 0.5 M H2SO4). Enantiomeric purities were
evaluated by comparison with literature values of specific rotations for the salts (42, 88, 89) used
for the resolutions and for the final acids (42, 45, 46, 77, 88, 90). A few cautions need to be
included here: there is a typo for the rotation of the salt of (S)-1a (88) (it should be +19.0, not
−19.0); the rotations for the salts of 1a and b given by Mosher in his Table 1 are completely
in error (42) (the values given are in fact Pettersson’s values for the acids (41)), and while not
published (to our knowledge), the specific rotation of the salts of 1e are ∼0, so the resolution
procedure described in the literature (88) is accurate but does not mention the reason one must
monitor the progress of the successive crystallizations by hydrolysis of a small fraction of the
salt – it is necessary to measure the specific rotation of the enantio-enriched 1e since the rotation
of the crystallized salt remains ∼0 throughout the successful resolution procedure. Further details
(including optical rotations) may be found in the supplementary data.
The acids were converted to the acid chlorides by reaction with neat oxalyl chloride (38) rather
than thionyl chloride (42) because the usual thionyl chloride procedure failed with naproxen
(1d), while oxalyl chloride gave complete (and much cleaner) reaction in 30 min. The other
carboxylic acids required 2 h for complete conversion. Following removal of the excess oxalyl
chloride and volatiles on a vacuum line, the acid chlorides were used without further isolation
in the next step (38). Conversions to the amides 4a–e were carried out as previously described
for 1c (42), and specific rotations have all been reported (45, 76, 77); however, work-up details
differed significantly from that described (42) and may be found with the compound data in the
supplementary data.
4.2. Synthesis of PADS analogs: (S,S)-di-2-phenylpropanoyl disulfide ((S,S)-2a)
The following procedure is representative of the method used for 2a–d. An aqueous solution of
sodium disulfide was prepared by heating a mixture of sulfur (0.050 g, 1.6 mmol) and sodium
sulfide nonahydrate (0.375 g, 1.56 mmol) in water (1.5 ml) at 90◦C for 15 min with stirring. After
cooling the aqueous solution, hexadecyltributylphosphonium bromide (0.071 g, 0.14 mmol) and
4 ml of toluene were added. With vigorous stirring at rt, a solution of (S)-2-phenylpropanoyl
chloride (0.350 g, 2.08 mmol) dissolved in 1 ml of toluene was added dropwise over 2–3 min.
After 20 min of stirring, the reaction solution was transferred to a separatory funnel with an
additional 5 ml of toluene. The aqueous layer was separated and the organic layer washed with
5 ml of H2O, and then dried with MgSO4. The solvent was removed on a rotary evaporator and the
crude product was passed through a pad of silica gel eluting with CH2Cl2. The UV-active material
moving with the solvent front was collected and the solvent evaporated to afford the product
as a pale white solid (0.31 g, 90% yield). The compound was crystallized from hot methanol
26
to give white crystals of 2a (0.18 g, 53% yield). mp 57–58◦C; [α]D + 370.2 (c 0.55, CH2Cl2);
1
HPLC >99.9% (S, S), <0.1% (R, R), <0.1% meso; IR (KBr, cm−1): 1735, 1720; H NMR
(400 MHz, CDCl3): δ 7.38–7.25 (m, 5H), 4.06 (q, 3JHH = 7.1 Hz, 1H), 1.58 (d, 3JHH = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): 195.2, 138.4, 129.0, 128.3, 128.0, 53.6, 18.6 ppm; HRMS
(ESI): Calcd. for C18H22NO2S2 [M + NH4]+: 348.1092, found 348.1090.
4.3. Synthesis of thioamides
4.3.1. (S)-2-Phenylpropanethioamide ((S)-5a)
The following procedure is representative of the method used for 5a, b, d, and e. Under a nitrogen
atmosphere, a mixture of P4S10 (0.647 g, 1.46 mmol) and Na2CO3 (0.156 g, 1.47 mmol) in 70 ml

Journal of Sulfur Chemistry 209
of dry THF was stirred at rt for 1.5 h. To the resulting clear yellow solution was added a solution
of (S)-4a (0.320 g, 2.14 mmol) dissolved in 10 ml of THF. The reaction solution was stirred at rt
for ∼24 h and then the solvent was removed on a rotary evaporator to give a gum. The gum was
then dissolved in 50 ml of CH2Cl2 and washed in a separatory funnel with 10 ml of 5% NaHCO3
and then with 20 ml of brine. The organic layer was removed, dried with anhydrous MgSO4, and
the solvent was again removed on a rotary evaporator to give a gum. The gum was taken up in
6 ml of benzene and then 30 ml of petroleum ether (30–60◦) was added to give a turbid solution
which was cooled in a freezer at −18◦C to give (S)-5a as a white solid (0.33 g, 93% yield).
27
mp 76–78◦C; [α]D + 80.0 (c 0.59, C6H6); HPLC 98.2% (S), 1.8% (R); IR (KBr, cm−1): 3489,
3419, 3371, 3276, 3158, 1620, 1594; 1H NMR (400 MHz, CD3CN): δ 7.94 (br s, 1H), 7.70 (br
s, 1H), 7.42–7.24 (m, 5H), 4.04 (q, 3JHH = 8.0 Hz, 1H), 1.54 (d, 3JHH = 8.0 Hz, 3H); 13C NMR
(100 MHz, CD3CN): 213.7, 143.5, 129.5, 128.4, 128.1, 53.2, 21.7 ppm; HRMS (ESI): Calcd. for
C9H12NS [M + H]+: 166.0690, found 166.0684.
4.3.2. (R)-3-Methyl-2-phenylbutanethioamide ((R)-5c)
Under a nitrogen atmosphere, a solution of (R)-4c (0.507 g, 2.86 mmol) in 10 ml of THF was
added to a solution of Lawesson’s reagent (see Scheme 2; 1.16 g, 2.87 mmol) in 30 ml of THF.
The reaction mixture was stirred at rt for ∼24 h and then the solvent was evaporated on a vacuum
line. The resulting gum was dissolved in 50 ml of EtOAc and washed in a separatory funnel with
10 ml of 5% NaHCO3. The organic layer was removed, dried with anhydrous MgSO4, and the
solvent was removed on a rotary evaporator to give a gum. The gum was dissolved in 3:1:0.01
EtOAc/hexanes/Et3N and passed through a pad of neutral alumina (Brockmann I) pre-washed
with the same solvent mixture. All the UV-active material moving with the solvent front was
collected and crystallized from 1:9 benzene/petroleum ether to afford (R)-5c as a white solid
30
(0.26 g, 48%). mp 99–101◦C; [α]D − 84.0 (c 0.62, C6H6); HPLC 88.9% (R), 11.1% (S); IR (KBr,
cm−1): 3497, 3445, 3380, 3279, 3164, 1622, 1595; 1H NMR (400 MHz, CDCl3): δ7.87 (br s, 2H,),
3
3
7.48–7.23 (m, 5H), 3.38 (d, JHH = 11.0 Hz, 1H), 2.62–2.49 (m, 1H), 1.03 (d, JHH = 6.5 Hz,
3
3H), 0.695 (d, JHH = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): 212.7, 141.6, 129.5, 129.2,
128.1, 68.2, 33.4, 21.5, 20.7 ppm; HRMS (ESI): Calcd. for C11H16NS [M+H]+: 194.1003, found
194.0996.
4.4. Synthesis of MEDITH analogs: (S)-5-(1-(6-methoxynapthalen-2-yl)ethyl)-3H-1,2,4-
dithiazol-3-one ((S)-6d)
In a nitrogen-filled glove box, a solution of thioamide (S)-5d (0.1019 g, 0.4153 mmol) and
pyridine (0.0748 g, 0.946 mmol) in 10 ml of ether was added at rt to a solution of chlorocarbonyl-
sulfenyl chloride (0.0695 g, 0.531 mmol) in 4 ml of ether. After stirring for ∼2 min, TLC (3:1
hexane/EtOAc) indicated the complete conversion of 5d to 6d. The pyridinium chloride was fil-
tered out and the solvent was removed using a vacuum pump to give a gum. The gum was dissolved
in ∼2 ml of ether and hexane was added until the solution became turbid (∼6 ml). The resulting
turbid solution was placed in the glove box freezer (−32◦C) overnight to give 6d as a white solid
28
after filtration and rinsing with hexane (0.12 g, 92% yield). mp 84–86◦C; [α]D + 54.0 (c 0.50,
C6H6); HPLC 94.9% (S), 5.1% (R); IR (KBr, cm−1): 1713, 1536; 1H NMR (400 MHz, CD3CN):
δ 7.17–7.87 (m, 6H), 4.57 (q, 3JHH = 7.1 Hz, 1H), 3.90 (s, 3H), 1.83 (d, 3JHH = 7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3): 201.2, 188.3, 159.3, 135.63, 135.55, 130.5, 129.7, 128.6, 128.5, 127.7,
120.4, 106.8, 56.1, 48.0, 20.9 ppm; HRMS (ESI): Calcd. for C15H14NO2S2 [M+H]+: 304.0466,
found 304.0466.

210 J.A. Mukhlall et al.
Acknowledgements
J.A.M. and W.H.H. thank Queens College for the purchase of HPLC equipment and the City University of New York
PSC-CUNY Research Award Program for the financial support.
Supplementary data
Experimental procedures for the synthesis of 1b, resolution of 1e, synthesis of 4a and d and data for 4a–e; tables
of observed and literature specific rotations of 1, the salts used for resolutions, and 4; experimental data, spectra, and
HPLC chromatograms for new compounds; coordinates from DFT calculations; details of the structure determination.
Supplementary data associated with this article can be found in the online version.
Notes
1. The usual name quoted in the literature, 3-methyl-1,2,4-dithiazolin-5-one, appears to us to be in error; the parent
ring system is fully unsaturated (hence the “ol” ring termination) and the position of the unsaturation is indicated
by giving the H the lowest available number.
2. The highest de’s for phosphite triester sulfurization with the disulfides reported here for RPS and SPS phosphoroth-
ioates were 14.7% and 7.9%, respectively.
3. Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC 779771 and 779772. Copies of
the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax:
+44-1223-336033 or Email: deposit@ccdc.cam.ac.uk).
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